Method and apparatus for evaluating values representing a mass or a concentration of a substance present within the body of a patient

ABSTRACT

The present invention relates to a method for evaluating a value representing the mass or the concentration of a substance comprised by a tissue or a bodily fluid of a patient, the method including the steps of a) determining a relation between one or more calculated or measured value(s) reflecting the mass or the concentration and a distribution space of the patient or an approximation thereof, and b) assessing whether the relation fulfils a criterion. The present invention further relates to systems and computer programs for performing this method.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a 371 national phase application of PCT/EP2010/005480, filedSep. 7, 2010, claiming priority to European Patent Application No.09011550.2, filed Sep. 9, 2009.

FIELD OF INVENTION

The present invention relates to a method for evaluating a valuerepresenting the mass or the concentration of a substance comprised by atissue or a bodily fluid of a patient, the method comprising the stepsof a) determining a relation between one or more calculated or measuredvalue(s) reflecting the mass or the concentration and a distributionspace of the patient or an approximation thereof, and b) assessingwhether the relation fulfils a criterion. It relates further to acontroller, an apparatus and a device for carrying out the presentinvention, further to digital storage means, a computer program product,and a computer program.

BACKGROUND OF THE INVENTION

In certain situations the mass or the concentration of a substance thatis present in a patient's body has to be checked or monitored—e.g., bythe physician in charge—be it for diagnostic reasons only or because thepatient's state needs to be actively controlled by amending eitherconcentration or mass of the substance. Hemoglobin (Hb) is such asubstance among many others.

In practice, the concentration of hemoglobin (Hb, also known as Hgb,being the iron-containing oxygen-transport metalloprotein in the redblood cells) is measured by means of blood samples to assess the anemiastate of the patient. Values below given thresholds are usuallyconsidered as a sign for the manifestation of “anemia” being defined asa decrease in normal number of red blood cells (RBCs) or less than thenormal quantity of hemoglobin in the blood.

SUMMARY OF THE INVENTION

By means of the present invention a method of evaluating a valuereflecting the mass or the concentration or the volume of a substance issuggested. Also, a controller for carrying out the method according tothe present invention is provided, as well as an apparatus, a devicecomprising a controller, digital storage means, a computer programproduct, and a computer.

The method according to the present invention is defined by the featurecombination of claim 1. Accordingly, in one aspect of the presentinvention, an evaluation—or a method for evaluating—of a valuerepresenting the mass or the concentration or the volume—or changesthereof, respectively—of a substance comprised by a tissue or a bodilyfluid of a patient comprises the step of determining a relation betweenone or more calculated or measured value(s) reflecting the mass or theconcentration or the volume of the substance comprised by the tissue orthe bodily fluid on the one hand, and one or more calculated or measuredvalue(s) reflecting a distribution space (or changes thereof) of thepatient or an approximation thereof on the other hand, and assessingwhether the relation fulfils at least one criterion.

The patient can be either a human being or an animal. The patient may besound or ill. The patient may be in need of medical care or not.

The controller according to the present invention is defined by thefeature combination of claim 17. Accordingly, in another aspect of thepresent invention, the controller is configured to carry out the methodaccording to the present invention.

The apparatus according to the present invention is defined by thefeature combination of claim 18. Accordingly, in another aspect of thepresent invention, the apparatus comprises means for obtaining a valuerepresenting the volume, the mass or the concentration of a substanceand/or means for obtaining a value representing the distribution space,or changes thereof, respectively, and at least one controller accordingto the present invention.

The device according to the present invention is defined by the featurecombination of claim 22 for treating the blood of a patient.Accordingly, in another aspect of the present invention, the devicecomprises at least one controller according to the present invention orat least one apparatus according to the present invention.

The digital storage means according to the present invention is definedby the feature combination of claim 25. Accordingly, in another aspectof the present invention, the digital storage means, in particular adisc, CD, or DVD, has electrically readable control signals which areable to interact with a programmable computer system such that a methodaccording to the present invention will be executed.

The computer program product according to the present invention isdefined by the feature combination of claim 26. Accordingly, in anotheraspect of the present invention, the computer program product has aprogram code stored on a machine readable data medium for executing amethod according to the present invention when executing the programproduct on a computer.

The computer program according to the present invention is defined bythe feature combination of claim 27. Accordingly, in another aspect ofthe present invention, the computer program has a program code for theexecution of a method according to the present invention when executingthe program on a computer.

It is noted that whenever it is referred to mass or concentration orvolume of a substance in the present specification, changes thereof arealso contemplated, be it expressly mentioned or not.

Embodiments can include one or more of the following features.

In some embodiments, a calculated or measured state reflecting both themass—or the concentration of a substance—and a distribution space of thepatient is a pair of values of the type “(x; y)” with x representing themass or the concentration—or changes thereof—and y representing thedistribution space. Preferably, both x and y results from measurementsperformed at the same time (e.g., same minute, same hour, same day, sameweek, same month, same stay or visit at the hospital, etc.)—orcalculations based on results of such measurements.

In certain embodiments, the method includes using values reflecting themass or the concentration that was obtained from at least one urinesample.

In some embodiments, the method includes using values reflecting themass or the concentration that was obtained from at least one bloodsample.

In certain embodiments, the blood sample has been taken from anextracorporeal blood circuit, in other embodiments from a blood vesselof the patient.

In some embodiments, the method includes using values reflecting themass or the concentration that was obtained from at least one tissuesample or at least one saliva sample.

In certain embodiments, the values may also have been obtained fromwhole body measurements, or from part body measurements for measuringbody contents directly (and not by means of indirect methods such asurinalysis).

In some embodiments, the whole body measurement is directed to themeasurement of radioactive substances (such as, e.g., potassium) bymeans of a whole body counter as is known from the prior art. Upon suchwhole body measurement, the patient is isolated from the radioactivebackground activity by appropriate means such as a chamber shielding thepatient positioned within the chamber from radioactive activity fromoutside. Knowing the activity of the radioactive substance to bemeasured, and also knowing the invariable or constant ratio between theradioactive substance and the non-radioactive substance comprised by thebody of the patient, it is possibly to determine the whole body contentof the substance in question.

In some embodiments, assessing whether the relation fulfils at least onecriterion means determining whether or not the relation fulfilscertain—predetermined or during executing the method according to thepresent invention determined—demands or requests (with “demand” and“request” being alternatives, examples or synonyms for “criteria” in thecontext of the present invention).

For example, when the relation is expressed in numbers, the criterionmay be one or more threshold values, so that the relation fulfils thecriterion if the number expressing the relation is higher (or lower)than a threshold, or between two or more thresholds. Similarly, when therelation is expressed as a symbol or a range or a curve in a graphic,the criterion may be expressed as a range in the graphic, so that tofulfil the criterion the relation may be above, in or below apredetermined range in a graphic, etc. These examples should, of course,not be understood to limit the present invention to these embodiments.

In certain embodiments, the relation may be a ratio of values. Forexample, it may be expressed by “concentration (or mass or change ofconcentration or change of mass)” over “distribution space (or anapproximation of the distribution space)”. In one embodiment, therelation is expressed by “concentration of Hb over relativeoverhydration”, with relative overhydration being related to thedistribution space.

In some embodiments, the distribution space is a body fluid. In certainembodiments, the distribution space is body tissue or the body weight orthe total body mass. In other embodiments, the distribution space is notthe body weight or not the total body mass. In some embodiments, thedistribution space is a combination of a body fluid and a body tissue.In some embodiments, the distribution space is a space that comprisesthe substance at issue. In certain embodiments, the distribution spaceis the space where the major part of the substance at issue is found inthe body of the patient. In some embodiments, the distribution space isthe only space of the body of the patient where the substance at issueis found.

In certain embodiments, the distribution space is defined as the bloodvolume (BV). The distribution space may also be defined as the ECW(extracellular water), the extracellular volume or fluid or mass of thebody, the ICW (intracellular water), the intracellular volume or fluidor mass of the body, the plasma volume, the TBW (total body water), theliquor, the volume of edema, lymph, urine, the total cell mass or anyother bodily fluid or volume, and also combinations thereof. Also, thedistribution space within the meaning of the present invention can beany ratio of volumes as mentioned before, e.g. ECW/ICW, etc.

In some embodiments, the distribution space is defined as the musclemass or volume. It can also be defined as the fat mass or volume, thebone mass or volume, etc.

In certain embodiments, the mass or the concentration of the substanceis an indicator of an anemia state of the patient.

The some embodiments, the indicator of an anemia state is the total massor the concentration of hemoglobin (Hb) or changes thereof over time,etc.

In certain embodiments, the concentration or the mass is directlymeasured, e.g., from blood samples or by means of optical methods, e.g.,without having drawn blood from a vessel as it is known in the art. Inaddition, or alternatively, the values at issue may be derived fromother values, parameters, etc. which allow a correct calculation or atleast a sufficient approximation of the substance, such as hemoglobin(Hb) or the hemoglobin (Hb) state.

In some embodiments, the indicator of an anemia state is the hematocrit(Hct), with the hematocrit (Hct) being understood also as aconcentration within the present invention.

In certain embodiments, the anemia state of the patient is expressed byonly one value such as a Hb concentration, or the Hct, etc.

In certain embodiments, the substance is comprised by the groupcomprising at least any protein produced naturally in the body of thepatient, in particular hemoglobin, albumin, insulin, glucose, CRP,hormones, total protein; cells (e.g., leucocites), electrolytes, andnon-endogeneous substances, in particular pharmaceutically-effectivesubstances like cytostatika, non-physiologic markers such as deuterium,etc.

In some embodiments, the distribution space is approximated based onmeasurements of the hydration state of the patient.

In certain embodiments, the distribution space is approximated,calculated or defined based on measured values and/or calculationsreflecting the overhydration (OH) or the relative overhydration (relOH:overhydration (OH) over extracellular water (ECW)), etc. of the patient.As regards a definition of overhydration (OH) it is referred to in WO2006/002685 A1, where OH equals a*ECW+b*ICW+c*body weight. Therespective disclosure of WO 2006/002685 A1 is hereby incorporated by wayof reference. It is to be understood that OH can be determined indifferent ways, all of which are known to the person skilled in the art.One of those methods comprises the measuring of a dilution and thecalculation of OH based thereon.

What has been described with reference to hemoglobin (Hb) regardingconcentration, change over time, values, calculation, approximation,etc. is meant to apply to the hematocrit (Hct), the blood volume (BV),the overhydration (OH), and the relative overhydration (relOH), as well.

In some embodiments, the distribution space of the patient may beexpressed by an age corrected overhydration or relative overhydration(relAEOH). In doing so, certain effects, e.g. due to age, can beeliminated for achieving more relevant values.

In certain embodiments, the distribution space of the patient may bedetermined or defined as overhydration (OH) over extracellular water(ECW) or may be graphically displayed in this way.

In some embodiments, the distribution space of the patient is expressedby only one value, in particular a value having the dimension liter (L).

In certain embodiments, the distribution space is measured orapproximated before dialysis or based on pre-dialysis values of thepatient.

In some embodiments, pre-dialysis (pre-Dx) values or calculations may bedata obtained immediately, i.e., moments or minutes, before starting thenext dialysis treatment. The invention is, however, not limited to this.Data can also be obtained at any other point of time. Pre-Dx data appearto be more stable than others. Using them can therefore be of advantage.

In certain embodiments, a target range is defined in a diagramrepresenting both the mass or the concentration or the volume of thesubstance of changes thereof, and the distribution space of the patientor an approximation thereof. The target range may alternatively be atarget area. The diagram may alternatively be a plot. The diagram may bea Cartesian coordinate system, also called a “rectangular coordinatesystem.” In a graphic illustration of the diagram, the mass or theconcentration or the volume of the substance or changes thereof can beshown over the distribution space or vice versa.

In some embodiments, the criterion is a threshold or a combination ofmore than one threshold.

In certain embodiments, the at least one criterion is preset orpredetermined.

In some embodiments, the at least one criterion is variable.

In certain embodiments, the method further includes determining thecriterion.

In some embodiments, the criterion is determined during executing themethod according to the present invention.

In certain embodiments, a regression line is calculated based onmeasured values or calculated results each reflecting both a mass (or aconcentration or a volume or changes thereof, respectively) and adistribution space, and assessing a position between the regression lineand the target range relative to each other. Relative to each other canbe understood as “above”, “below” besides”, “within”, “crossing” and soforth. The relative position can be attributed certain degrees ornumeral value.

In some embodiments, the criterion can be based on a classification, inparticular a Bayes-classification. Also, it is contemplated to define acriterion based on a Fuzzy-Logic. A classification may also be achievedby means of Nearest Neighbour, and by neural networks, etc.

In certain embodiments, a regression line is calculated based onmeasured values or calculated results. The regression line can expressany appropriate function.

In some embodiments, the values for mass or concentration and for thedistribution space are such obtained at one occasion. “One occasion” maybe understood as a specific time, e.g. a range of a few minutes orhours. It may also be a day or the duration of one treatment, inparticular one dialysis treatment. “One occasion” may also be understoodas the time the patient spends in the clinic for treatment.

In certain embodiments, the method comprises classifying the results ofthe assessment.

In some embodiments, the method according to the present inventionincludes plotting or drawing the regression line and/or the target rangewhere necessary.

In certain embodiments, the method includes displaying in a table, aspreadsheet or a chart, etc. whether the criterion has been fulfilled(or not).

In some embodiments, it is assessed whether or not the criterion isfulfilled based on only two values: one value reflecting the mass or theconcentration of the substance and one value reflecting the distributionspace.

In certain embodiments, the two values are represented by only one pointin a appropriate graphic.

In some embodiments, the assessment may be carried out solely with thatone point or those two values.

In certain embodiments, one or all values considered for determining therelation reflect the corresponding mass, volume, concentration in anabsolute manner. That is, changes over time may remain unconsidered. Anyvalue reflecting mass, concentration or volume may be, hence, a staticone.

Also, in some embodiments, the value reflecting the mass, concentrationor the volume of a substance is not arrived by subtracting of values,e.g., a first concentration value from a second concentration value,etc.

In certain embodiments, for determining the relation no time constant ortime variable or parameter is considered or included. In particular, nomass, concentration or volume value is multiplied by a time value.

In some embodiments, the slope of a regression line is also consideredupon the step of assessing. The slope may be estimated or may be(approximately) known from earlier measurements from the same patient ora corresponding patient or collective of patients (sound or ill).

In certain embodiments, the y-offset of a regression line is alsoconsidered upon the step of assessing. “y” may relate to the mass,concentration or volume of the substance, or to the hydration value,e.g. relOH when displayed in a diagram, e.g. in a Cartesian coordinatesystem.

In some embodiments, the value reflecting the distribution space ismeasured in liters (L).

In certain embodiments, the mass or the concentration (or changesthereof) and the distribution space of the patient are calculated and/ormeasured. The measurement and calculations may be carried out by meansof any method known in the art, using any device suitable therefor. Inparticular, in some embodiments, the respective data may be obtained bymeasuring Hb from blood samples and/or from blood comprised inextracorporeal blood lines by means of an appropriate monitor. Themeasurements can be made by measuring the optical properties of theblood by optical sensors and/or by assessing acoustic properties liketransit times and/or propagations velocities of ultrasonic pulses byultrasonic sensors.

For determining the hydration state any appropriate monitor can be used,such as monitors based on bioimpedance or dilution techniques.

The monitor for obtaining data related to the hydration state can be amonitor as described in WO 2006/002685 A1. The respective disclosure ofWO 2006/002685 A1 is hereby incorporated in the present application byway of reference. Of course, the present invention must not beunderstood to be limited to monitors determining the hydration state ofthe patient by bioimpedance measurements as is described in WO2006/002685 A1. Other methods known in the art such as dilutionmeasurements and also any other method known to the skilled person arealso contemplated and encompassed by the present invention as well.

In some embodiments, a dosage of a medicament to be administered to apatient for improving his anemia state is determined or adjusted basedon the result of assessing whether the criterion is fulfilled or not.

In certain embodiments, the distribution volume should be adjusted. Thiscan be achieved by administration of substances such as diuretics and/orby dialysis, e.g. ultrafiltration. In some embodiments, apharmaceutically effective substance is administered. In certainembodiments, the result of the assessment as regards the criterion isoutputted in form of an advise of how to treat the patient.

In some embodiments, the criterion is set or determined orpre-determined.

In certain embodiments, the apparatus is a monitor for obtaininginformation concerning distribution space or an approximation thereof,e.g., the hydration state. An example of such a monitor is describedabove. For avoiding unnecessary repetition, it is generally referred tohydration monitors that yield results reflecting the hydration statebased on bioimpedance signals, dilution methods or any other methodknown in the art.

In some embodiments, the apparatus comprises furthermore an outputdevice for outputting results provided by the controller. The outputdevice may be a monitor having a display, a plotter, a printer or anyother means for providing an output.

In certain embodiments, the apparatus comprises a monitor for measuringHb concentrations (e.g., in [g/dl]) and/or for determining the bloodvolume by means of any monitor as described in “Replacement of RenalFunction by Dialysis” by Drukker, Parson and Maher, Kluwer AcademicPublisher, 5^(th) edition, 2004, Dordrecht, The Netherlands, on pages397 to 401 (“Hemodialysis machines and monitors”), the respectivedisclosure of which is hereby incorporated by way of reference.

In some embodiments, the monitor is configured to measure the bloodvolume and/or the concentration of the substance—in particular Hb—bymeans of measuring an electrical conductivity.

In certain embodiments, the monitor is configured to measure the bloodvolume and/or the concentration of the substance—in particular Hb—bymeans of measuring an optical density.

In some embodiments, the monitor is configured to measure the bloodvolume and/or the concentration of the substance—in particular Hb—bymeans of measuring a viscosity.

In certain embodiments, the monitor is configured to measure the bloodvolume and/or the concentration of the substance—in particular Hb—bymeans of measuring a density.

In some embodiments, the monitor comprises one or more correspondingprobes and/or one or more sensors for carrying out the measurements suchas electrical conductivity sensors, optical sensors, viscosity sensors,density sensors, and the like.

In certain embodiments, the device may be used for treating a patient bymeans of dialysis.

In other embodiments, the device may be used for treating a patient (orthe patient's blood) by hemofiltration, ultrafiltration, hemodialysis,etc.

The embodiments may provide one or more of the following advantages.

By means of the present invention, the merit of parameters or valuesrepresenting certain states of the patient caused or accompanied bycertain values reflecting the mass or concentration or the substance(such as the anemia state)—which parameters can be deteriorated by thevolume of the distribution space or the actual hydration state—can bedetermined in an easy manner.

For example, in current practise it is unclear whether the unphysiologicconcentration of a substance (e.g., very low hemoglobin levels of <8g/dl) in a patient (e.g., with cardiac or renal impairment) should becorrected by modifying metabolism (e.g., by administeringerythropoisesis stimulation agents) or by correcting its distributionvolume or space (e.g., by ultrafiltration therapy or by administeringdiuretic drugs), or rather a combination of both. In other words, themeasured Hb concentration may appear “artificially” altered or diluted,to different degrees, depending on the degree of overhydration(hyperhydration) or underhydration (hypohydration).

In case of severe overhydration, the blood volume may be expanded beyondnormal levels, which leads to a decrease in Hb concentration even thoughthe absolute red cell mass would be appropriate for a normal hydrationstatus. As an example, an overhydration of 3 liter (L) may lead to anincrease of 1 liter (L) in blood volume (BV) and, thus, 2 liter (L) inthe interstitial space. Since the relative change in BV and OH is thesame because of this typical 2:1 relationship it is possible to usevalues representing overhydration (which is more easily measurable thanthe blood volume) instead of blood volume for the criterion basedevaluation. Assuming a typical blood volume (BV) of 5 L, this wouldrepresent an increase of 20%. A 20% decrease in Hb concentration wouldlead, e.g., from 11.5 to 9.2 g/dl. Such a low Hb level would lead to anincrease in Erythropoietin (EPO) medication. Thus, the patient wouldpossibly benefit more from a correction of his overhydration (OH) thanfrom correction of Hb by means of pharmaceuticals.

All or some of the advantages mentioned above may also found when thepresent invention is applied to other substances than Hb which was onlyused here by way of example.

Other aspects, features, and advantages will be apparent from thedescription, figures, and claims. The following example relates to Hb asthe substance in question and the distribution space is approximated bythe measured relative overhydration of the patient, However, the presentinvention must not be understood to be limited to this example.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a plot of states reflecting both an anemia state and ahydration state of the patient in a Hb-overhydration-diagram;

FIG. 2 shows a plot corresponding to the plot in FIG. 1, revealing dataof another patient;

FIG. 3 shows a plot corresponding to the plot in FIG. 1, revealing dataof another patient;

FIG. 4 shows a plot corresponding to the plot in FIG. 1 in a moregeneral illustration;

FIG. 5 shows a plot corresponding to the plot in FIG. 1, revealing dataof yet another patient;

FIG. 6 shows a plot corresponding to the plot in FIG. 1, revealing dataof yet another patient;

FIG. 7 shows a plot corresponding to the plot in FIG. 1, revealing dataof yet another patient;

FIG. 8 shows a plot corresponding to the plot in FIG. 1, revealing dataof the patient of FIG. 5;

FIG. 9 shows a plot corresponding to the plot in FIG. 1, revealing dataof yet another patient;

FIG. 10 shows a plot corresponding to that of FIG. 1, revealing data ofonly one measurement;

FIG. 11 shows a first apparatus comprising a controller for carrying outthe method according to the present invention; and

FIG. 12 shows a second apparatus comprising a controller for carryingout the method according to the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the result of 19 measurements reflecting both the patient'sanemia state and hydration state plotted in a diagram. The diagram is aCartesian coordinate system showing Hb over relAEOH (relativeoverhydration, corrected for age). The results of the 19 measurementsobtained from the patient in question (here anonymized as “Subject 15”)are illustrated by means of small circles 1.

A regression analysis has been carried out based on the result of the 19measurements. The obtained result has been added in FIG. 1 as regressionline 3.

In FIG. 1, a target range 5 is further shown. The shape and position oftarget range 5 has been selected or determined based on experience anddata of individuals by way of example. The invention must however not beunderstood to be limited to this. Both shape and position of the targetrange 5 can be determined differently if need should be. In particular,the target range can reflect findings from earlier measurement of thesame patient. Further, the target range can reflect findings based onmeasurement of patients being a comparable situation as the patient atissue, e.g., suffer from the same disease.

The criterion to be fulfilled in the example of FIG. 1 is whether or notthe regression line 3 crosses the target range 5 or not. As can be seenfrom FIG. 1, the criterion is clearly met in FIG. 1 as the regressionline 3 obviously crosses the target range 5, see a portion 3′ ofregression line 3.

In the example of FIG. 1, the anemia state is reflected by Hbconcentrations (in [g/dl]) obtained by means of any monitor as describedin, e.g., “Replacement of Renal Function by Dialysis” by Drukker, Parsonand Maher, Kluwer Academic Publisher, 5^(th) edition, 2004, Dordrecht,The Netherlands, on pages 397 to 401 (“Hemodialysis machines andmonitors”) as is also noted above. Again, the respective disclosure ofpages 397 to 401 is hereby incorporated by way of reference. The firstvalue was obtained after a dialysis treatment has been started. It isnoted that the monitor discussed here can be used for monitoring ordetecting the blood volume (or changes thereof) with the blood volumebeing considered as another distribution space within the meaning of thepresent invention.

Also, in the example of FIG. 1, the hydration state is reflected by arelative overhydration (overhydration (OH) over extracellular water(ECW)), measured by means of a monitor as referred to above withreference to WO 2006/002685 A1. These values have been obtained beforestarting the dialysis treatment (“pre-Dx”).

As regards any value referred to in here, time averaged values (as forHb) can be used. Also, analysis revealed that the first value duringtreatment has the best correlation to weight changes and OH changes. Thereason may be that towards the end of a treatment a lot of perturbationexists in the micro- and macrocirculation. It may be therefore thatafter 30 minutes without ultrafiltration (to make sure refilling hasstopped) more reliable values can be measured.

Target range 5 may be understood as possible pre-Dx target range forboth Hb and relOH.

As can be seen from FIG. 1, as the patient's hydration status wasdecreased, Hb concentration went up because of the (reversed) dilutioneffect; the red cell mass stayed constant, and so did the total Hb mass(not the concentration).

Since the regression line 3 which indicates a significant correlationbetween Hb and relOH moves trough the target range 5, a normalization ofhydration by means of fluid management will automatically normalize Hbas well. Further interventions for managing the anemia state of thepatient such as administration of EPO or an adoption thereof seem not tobe necessary.

FIG. 2 shows a plot like that of FIG. 1, revealing data of anotherpatient (“Subject 22”). In FIG. 2, the regression line 3″ passes belowthe target range 5. The criterion applied here (i.e., the regressionline 3 has to cross or intersect the target range 5) is not fulfilled.Hence, it appears that the values representing the anemia state of thepatient will not return to normal once the hydration state has beenbrought back to normal. Hence, the patient will probably benefit fromadministration of substances increasing his Hb concentration back tonormal, or from increasing the dosage of such substances if he alreadyreceives/takes medication.

FIG. 3 shows a plot like those of FIG. 1 or FIG. 2, revealing data ofyet another patient (“Subject 69”). In FIG. 3, the regression line 3′″passes above the target range 5. Again, the criterion applied here isnot fulfilled. Again, it appears that the values representing the anemiastate of the patient will not return to normal once the (over-)hydrationstate has been brought back to normal. Hence, in case the patient isbeing administered substances increasing his Hb concentration such asEPO, he most probably will benefit from reducing the dosage of thosesubstances.

As can be seen from FIG. 3, the result of the evaluation of the anemiastate of a patient according to the present invention depends very muchon how the criterion is (pre-)determined. If, for instance, thecriterion was defined to be fulfilled if only one, two or more resultsare found to be within a target range—instead of determining that aregression line has to intersect the target range as in the examples ofthe drawing—then the criterion had been fulfilled also in the exampleshown in FIG. 3.

What has been explained above with reference to FIG. 1 to FIG. 3 isschematically shown in FIG. 4 for any patient being administered EPO.FIG. 4 shows the general concept of how EPO dosage may be derived fromthe location (relative position) of the regression lines in the plot: Ifa regression line 3′″ is found, it is advised to decrease the EPOdosage. A regression line calculated based on results of measurementsdone after adaption (decrease) of the EPO doses will be a lower one asindicated by arrow 7′. If a regression line 3″ is found, the patientappears to benefit from high EPO doses. A regression line calculatedbased on results of measurements done after adaption (increase) of theEPO doses will be a higher one as indicated by arrow 7″.

It is noted that for determining the regression line, only a few initialmeasurements are needed—already one result or point may be enough.Results obtained from measurements done over a period of time of, e.g.,2-4 weeks will be sufficient.

As has been indicated in FIG. 5 by the shape of the target range 5, withthe shape of FIG. 5 being different to those of FIG. 1 to FIG. 4, it iseven possible to define a “target corridor 5′” for the dosage of apharmaceutical such as EPO. The target corridor 5′ is a more specificexample of the target range 5 known from FIG. 1 to FIG. 4. It differs inthat it has been adapted to the individual regression line slope of thepatient in question (here: of “Subject 141”). Shaped as shown in FIG. 5,the target corridor 5′ may contribute to allow early adjustment of EPOeven when normal hydration status has not yet been reached. This may beparticularly beneficial in respect of long time constants between EPOadministration and production of red blood cells (hematopoiesis). As canbe seen from FIG. 5, EPO dosage may be increased already at thebeginning of the dry-out-phase.

As can be seen from FIG. 5, the criterion for evaluating the anemiastate of a patient to be fulfilled according to the present inventioncan also be whether or not the slope or inclination of the regressionline is parallel to the extension or the main extension of a targetrange, in particular of a rectangular one. Also, the criterion can bewhether the regression line falls completely within the target range, orwhether the regression line does not cross certain, predeterminedportions or sides of the target range and so forth.

FIG. 6 to FIG. 9 show further examples of plots drawn from the resultsof Hb and hydration measurements obtained from yet other patients(“Subjects 73, 86, and 94”) and the patient of FIG. 5. The presetcriterion (i.e., the regression line 3 has to cross or intersect thetarget range 5) is not fulfilled for the patients of FIG. 8 and FIG. 9,whereas it is fulfilled for the patients of FIGS. 6 and 7.

From the figures it can be seen that if the patient's reference line orregression line crosses the reference range only the hydration stateshould be adjusted—if the reference or regression line passes above orbelow, metabolic processes should be addressed (e.g., with EPO).

FIG. 10 shows a plot like those of FIG. 1 or FIG. 2 displaying theconcentration of Hb [g/dl] over overhydration [L, or l], revealing dataof only one measurement being depicted by circle 1. As can be seen fromFIG. 10, no regression line 3 can be determined based on only onemeasurement. From FIG. 10 it is further understood that in certaincircumstances no regression line is required for assessing whether ornot the criterion (here: the measurement represented by circle 1 fallsinto the range 5 or not) is fulfilled. In any case, in the example ofFIG. 10 the preset criterion is not fulfilled.

As can be seen from any of the figures discussed above, whether thecriterion is met by certain anemia states and hydration states of therespective patient depends on how the criterion is set or determinedbeforehand.

FIG. 11 shows an apparatus 9 comprising a controller 11 for carrying outthe method according to the present invention. The apparatus 9 isconnected to an external database 13 comprising the results ofmeasurements and the data needed for the method according to the presentinvention. The database 13 can also be an internal means. The apparatus9 may optionally have means 14 for inputting data into the controller 11or into the apparatus 9. Such data may be information about the mass,the volume, the concentration of the substance as is set forth above.Such data input into the apparatus 9 may—additionally or instead—also beinformation about the distribution space of the patient or anapproximation thereof. Also, the criterion may be inputted by means ofthe input means 14. The criterion may, however, alternatively be storedin database 13 or any other storage. The criterion may be calculated ordetermined by the controller 11 or any other item comprised by theapparatus 9 or interconnected to it. The results of the evaluation,calculation, comparison, assessment etc. performed by the controller 11and/or the apparatus 9 can be displayed on the monitor 15 or plotted bymeans of a—not displayed but optionally also encompassed—plotter orstored by means of the database 13 or any other storage means. Thedatabase 13 can also comprise a computer program initiating the methodaccording to the present invention when executed.

In particular, the controller 11 can be configured for determining arelation between one or more calculated or measured value(s) reflectingthe mass or the concentration or the volume of the substance comprisedby a tissue or a bodily fluid and a distribution space of the patient oran approximation thereof, and for assessing whether the relation fulfilsat least one predetermined criterion.

As can be seen from FIG. 12, for corresponding measurements, theapparatus 9 can be connected (by means of wires or wireless) with abioimpedance measurement means 17 as one example of a means formeasuring or calculating the hydration state or an overhydration state.Generally, the means for measuring or calculating the hydration state oran overhydration state can be provided in addition to the externaldatabase 13 comprising the results of measurements and the data neededfor the method according to the present invention, or in place of theexternal database 13 (that is, as an substitute).

The bioimpedance measurement means 17 can be capable of automaticallycompensating for influences on the impedance data like contactresistances.

An example for such a bioimpedance measurement means 17 is a device fromXitron Technologies, distributed under the trademark Hydra™ that isfurther described in WO 92/19153, the disclosure of which is herebyexplicitly incorporated in the present application by reference.

The bioimpedance measurement means 17 may comprise various electrodes.In FIG. 12, only two electrodes 17 a and 17 b shown which are attachedto the bioimpedance measurement means 17. Additional electrodes are, ofcourse, also contemplated.

Each electrode implied can comprise two or more (“sub”-)electrodes inturn. Electrodes can comprise a current injection (“sub”-)electrode anda voltage measurement (“sub”-)electrode. That is, the electrodes 17 aand 17 b shown in FIG. 12 can comprise two injection electrodes and twovoltage measurement electrodes (i.e., four electrodes in total).

Generally spoken, the means for measuring or calculating the hydrationstate or an overhydration state can be provided by means of weighingmeans, a keyboard, a touch screen etc. for inputting the required data,sensors, interconnections or communication links with a lab, any otherinput means, etc.

Similarly, the apparatus 9 may have means 19 for measuring orcalculating means for obtaining a value reflecting the mass, the volumeor the concentration of the substance that can again be provided inaddition to the external database 13 already comprising the results ofmeasurements and the data needed for the method according to the presentinvention, or in place of the external database 13 (that is, as ansubstitute).

The means 19 can be provided as a weighing means, a keyboard, touchscreen etc. for inputting the required data, sensors, interconnectionsor communication links with a lab, a Hb concentration probe, any otherinput means, etc.

Again, it is noted that the figures relate to Hb/anemia state andrelOH/hydration state by means of examples showing how one embodimentaccording to the present invention may be carried out. They are not tobe understood as limiting.

What is claimed is:
 1. A method for evaluating a value representing amass or a concentration or a volume of a substance contained in a tissueor a bodily fluid of a patient, comprising the steps of: measuring thevalue representing the mass or the concentration or the volume of thesubstance contained in the tissue or the bodily fluid of the patient;determining, by a processor, a relation between: (a) the measured valuerepresenting the mass or the concentration or the volume of thesubstance contained in the tissue or the bodily fluid of the patient,and (b) a distribution space of the patient, the distribution spacebeing a body fluid, a body tissue, a body weight, a total body mass, acombination of the body fluid and the body tissue, or a space of thepatient, wherein the distribution space is based on calculated ormeasured values reflecting a relative overhydration (relOH) of thepatient or an absolute overhydration (OH) of the patient; assessing, bythe processor, whether the relation fulfils at least one criterion; andbased on the assessing whether the relation fulfills the at least onecriterion, adjusting the distribution space of the patient usingdialysis.
 2. The method according to claim 1, wherein the one or morecalculated or measured value(s) reflecting the mass, the volume or theconcentration of the substance was obtained from a sample selected fromthe group consisting of blood samples, urine samples, and tissuesamples.
 3. The method according to claim 1, wherein the substance isselected from the group consisting of proteins produced naturally in thebody of the patient, hemoglobin, albumin, insulin, glucose, C-reactiveprotein (CRP), and pharmaceutically-effective non-endogeneoussubstances.
 4. The method according to claim 1, wherein the mass or theconcentration of the substance or changes thereof is an indicator of ananemia state of the patient.
 5. The method according to claim 4, whereinthe indicator of the anemia state of the patient is selected from thegroup consisting of a concentration of hemoglobin, a total mass ofhemoglobin, a change in the concentration or in the total mass ofhemoglobin over time, a hematocrit, and a change in the hematocrit overtime.
 6. The method according to claim 1, wherein the distribution spaceof the patient is selected from a measured value of a blood volume or acalculated value of the blood volume.
 7. The method according to claim1, wherein the distribution space is measured or approximated before adialysis treatment or based on pre-dialysis values of the patient. 8.The method according to claim 1, further comprising the step of:defining a target range in a diagram reflecting (a) the mass or theconcentration of the substance or the approximation thereof and (b) thedistribution space or the approximation thereof.
 9. The method accordingto claim 8, further comprising the step of: calculating a regressionline based on either the measured or the calculated values reflectingboth (a) the mass or the concentration of the or an approximationthereof, and (b) the distribution space of the patient or anapproximation thereof; and determining any overlap between theregression line and the target range.
 10. The method according to claim1, further comprising the step of: at least one of calculating ormeasuring the values reflecting at least one of (a) the mass or theconcentration of the substance or an approximation thereof or (b) thedistribution space of the patient or an approximation thereof.
 11. Themethod according to claim 1, further comprising the step of: determiningthe at least one criterion.
 12. The method according to claim 1, whereinthe distribution space is measured or approximated during or after adialysis treatment.
 13. A system for evaluating a value representing amass or a concentration or a volume of a substance contained in a tissueor a bodily fluid of a patient, comprising a controller configured to:measure the value representing the mass or the concentration or thevolume of the substance contained in the tissue or the bodily fluid ofthe patient; determine a relation between: (a) the measured valuerepresenting the mass or the concentration or the volume of thesubstance contained in the tissue or the bodily fluid of the patient,and (b) a distribution space of the patient, the distribution spacebeing a body fluid, a body tissue, a body weight, a total body mass, acombination of the body fluid and the body tissue, or a space of thepatient, wherein the distribution space is based on calculated ormeasured values reflecting a relative overhydration (relOH) of thepatient or an absolute overhydration (OH) of the patient; assess whetherthe relation fulfils at least one criterion; and based on the assessingwhether the relation fulfills the at least one criterion, adjust thedistribution space of the patient using dialysis.
 14. The systemaccording to claim 13, further comprising a system configured to obtaina value reflecting a characteristic selected from the group consistingof the distribution space of the patient's body, the approximation ofthe distribution space of the patient's body, changes in thedistribution space of the patient's body, the mass of the substance,changes in the mass of the substance, the volume of the substance,changes in the volume of the substance, the concentration of thesubstance, and changes in the concentration of the substance.
 15. Thesystem according to claim 14, wherein the system configured to obtainthe value comprises a device configured to measure or calculate ahydration state or a degree of overhydration of the patient.
 16. Thesystem according to claim 14, wherein the system configured to obtainthe value comprises a device selected from the group consisting of adevice configured to measure weight, a device for configured todetermine a blood volume of the patient, a keyboard, a touch screen, anda device configured to measure or calculate at least one of theconcentration, the volume or the mass of the substance.
 17. The systemaccording to claim 13, further comprising an output device configured tooutput results provided by the controller.
 18. The system according toclaim 13, wherein the system is configured to treat a patient's blood.19. The system according to claim 18, wherein the system is configuredto treat the patient's blood by dialysis.
 20. The system according toclaim 19, wherein the system is configured to treat the patient's bloodby at least one of hemofiltration, ultrafiltration, or hemodialysis. 21.A non-transitory computer-readable medium with an executable programstored thereon, wherein the program instructs a programmable computersystem to perform the following steps for evaluating a valuerepresenting a mass or a concentration or a volume of a substancecontained in a tissue or a bodily fluid of a patient: measuring thevalue representing the mass or the concentration or the volume of thesubstance contained in the tissue or the bodily fluid of the patient;determining a relation between: (a) the measured value representing themass or the concentration or the volume of the substance contained inthe tissue or the bodily fluid of the patient, and (b) a distributionspace of the patient, the distribution space being a body fluid, a bodytissue, a body weight, a total body mass, a combination of the bodyfluid and the body tissue, or a space of the patient, wherein thedistribution space is based on calculated or measured values reflectinga relative overhydration (relOH) of the patient or an absoluteoverhydration (OH) of the patient; assessing whether the relationfulfils at least one criterion; and based on the assessing whether therelation fulfills the at least one criterion, adjusting the distributionspace of the patient using dialysis.
 22. The method according to claim1, further comprising: based on the assessing whether the relationfulfills the at least one criterion, adjusting a dosage of a medicamentthat is to be administered to the patient for improving an anemia stateof the patient.
 23. The method according to claim 1, wherein thedistribution space is adjusted by: (i) ultrafiltration, (ii)administration of pharmaceutically effective substances, or (iii) bothultrafiltration and administration of pharmaceutically effectivesubstances.
 24. The method according to claim 1, wherein thedistribution space is adjusted by administering pharmaceuticallyeffective substances comprising diuretics to the patient.